PROJECT SUMMARY/ABSTRACT: PROJECT 3 HELICOBACTER PYLORI AND STOMACH CANCER AMONG NATIVE AMERICAN POPULATIONS Helicobacter pylori (Hp) is a common gastric pathogen that is associated with the development of duodenal or stomach ulcers, stomach cancer, and mucosa associated lymphoid-tissue (MALT) lymphomas. While the overall incidence of gastric cancer has declined over time in the United States (US), there are clear racial and socioeconomic health disparities in gastric cancer rates and associated outcomes. This translational, multi- method project seeks to better understand the role of Hp infection in the development of stomach cancer among Native Americans (NA) of Northern Arizona where stomach cancer incidence rates are approximately three times as high compared to the general Arizona population and it is the leading cause of cancer-related mortality. Despite this high burden, social, environmental, and pathogen-associated risk factors remain unknown for this underserved population. While prevalence varies within populations, Hp prevalence within Navajo Nation is likely high. Our pilot study of 72 households found 59% of 108 participants were Hp positive by urea breath test (UBT) and 74% of households had at least one person positive. Furthermore, prior knowledge of Hp and its link to stomach cancer is low in these communities. However, 53% of Hp+ cases did seek care at the local urban Indian Health Service facility, indicating concern. Risk factors for Hp infection in this distinct population are not clearly defined nor are barriers to receiving diagnosis and treatment, precluding appropriate primary and secondary prevention strategies. Thus Aim 1 is a community-based study to identify factors associated with infection and barriers to self-referral to clinic. Since Hp subtypes may contribute to progression from infection to cancer and the prevalence of specific genotypes are unknown in this population, Aim 2 will focus on the distribution of Hp subtypes in the Navajo community members referred to clinic for endoscopy. The relationship between Hp infection and subsequent stomach cancer is related also to host immune response. Intestinal metaplasia and Spasmolytic Polypeptide-expressing metaplasia (SPEM) are histologic changes that presage gastric cancer development. SPEM is more intensively studied in mice than humans because it can be induced experimentally after introducing Helicobacter. Epithelial expression of the sonic hedgehog (Shh) ligand and mesenchymal activation of canonical Hedgehog signaling play essential roles in gastric homeostasis and recruitment of inflammatory cells. Our earlier studies found a subset of immune cells recruited to the gastric epithelium during infection become myeloid-derived suppressor cells (MDSCs), and this coincides with parietal cell atrophy and SPEM. Schlafens (SLFN) are a family of molecules strongly induced by type 1 interferons that correlate with immune cell quiescence. Using whole genome analysis of mouse cells, we identified a microRNA signature for this IFN-regulated immune cell in both metaplastic gastric tissue and serum of both infected mice and humans. Thus, in Aim 3 a miRNA signature will be analyzed in the gastric biopsies and compared to its presence in serum collected at time of endoscopy.